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GM-CSF-Induced Metal Sequestration and Histoplasma

GM-CSF 诱导的金属螯合和组织胞浆菌

基本信息

批准号：
10437747
负责人：
GEORGE S. DEEPE
金额：
$ 53.1万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437747
关键词：
Area Binding Bioinformatics Biological Biology Cathepsins Cell membrane Cells Cellular biology Central America Colony Stimulating Factor Activation Colony-Stimulating Factors Cytokine Activation Data Dendritic Cells Deposition Environment Enzymes Exhibits Funding Genotype Glycolysis Granulocyte-Macrophage Colony-Stimulating Factor Growth Histoplasma Histoplasma capsulatum Homeostasis Host Defense Human Immune Immune response Immunology Infection Interferons Interleukin-4 Investigation Knowledge Link Lung MT3 gene Mediating Mediator of activation protein Membrane Metabolic Metabolism Metalloproteins Metallothionein Metals Molds Mus Mycoses Organism PF4 Gene Pathogenicity Phagocytes Phagosomes Phase Phenotype Physiology Planet Earth Prevalence Production Property Proteome Reactive Oxygen Species Regulation Reproduction spores Role Shapes Soil South America T-Lymphocyte Trace metal Vacuole Work Yeasts Zinc adaptive immune response cytokine deprivation design extracellular fungus granulocyte immunoregulation in vivo insight interdisciplinary approach macrophage metabolic phenotype microbial disease monocyte novel novel strategies pathogenic fungus prevent respiratory response stressor transcription factor zinc thionein zinc-binding protein

项目摘要

The pathogenic fungus, Histoplasma capsulatum, is endemic to the Midwestern and Southeastern US and is the most frequent cause of respiratory fungal infection. The organism thrives within the intracellular environ- ment of monocytes (Mo) and macrophages (Mɸ) and has the capacity to establish a latent state. Employing a multidisciplinary approach including metallomics, immunology, cell biology and bioinformatics, our studies have identified novel functions of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 that help to explain their disparate effects on the growth of the fungus with Mo/Mɸ. GM-CSF deprives the organism of zinc intracellularly while concurrently boosting production of reactive oxygen species. The end result is killing of yeast cells. On the other hand, IL-4 promotes intracellular survival by fortifying the amount of zinc available to Histoplasma. Crucial to the activities of GM-CSF and IL-4 are metallothioneins (MTs), which store and donate zinc, and zinc transporters. They are a central node mediating the link between cytokine activation and effector function. For GM-CSF, MTs1 & 2 are essential whereas for IL-4, it is MT3. In this proposal, we will build on our work conducted during the last funding cycle and explore in depth how the MT- zinc axis regulates the activity of GM-CSF and IL-4 on human and mouse Mo/Mɸ. We have collected exciting data that glycolysis governs the expression of MTs1&2 in infected GM-CSF-stimulated Mo/Mɸ. On the other hand, MT3 tempers the glycolytic response in IL-4 activated in these cells. Aim 1 will decipher how glycolysis molds MT1&2 expression and intracellular Zn2+ distribution to bolster Mo/Mɸ effector function. Aim 2 will define the intracellular alterations in GM-CSF-activated Mo/Mɸ that deny the fungus access to zinc and the in vivo effect of MTs1&2 on host defenses exerted by these phagocytes. Aim 3 will elucidate the intersection of glycolysis and MT3 in shaping the physiology of IL-4 on Histoplasma-infected Mo/Mɸ. These studies will provide new insights into cytokine regulation of metabolism and metallobiology in Histoplasma-infected Mo/Mɸ.

致病性真菌，荚膜组织胞浆菌，是美国中西部和东南部的特有种。是呼吸道真菌感染的最常见原因。有机体在其中茁壮成长单核细胞 (Mo) 和巨噬细胞 (Mɸ) 的细胞内环境，并且有能力建立潜在状态。采用多学科方法，包括金属组学、免疫学、细胞生物学和生物信息学，我们的研究发现了粒细胞的新功能巨噬细胞集落刺激因子 (GM-CSF) 和白细胞介素 (IL)-4 有助于解释其作用 Mo/Mɸ 对真菌生长的影响不同。 GM-CSF 剥夺机体的锌细胞内同时促进活性氧的产生。最终结果是杀死酵母细胞。另一方面，IL-4 通过强化细胞内活性来促进细胞内存活。组织胞浆菌可利用的锌量。 GM-CSF 和 IL-4 的活性至关重要的是金属硫蛋白（MT），储存和提供锌以及锌转运蛋白。他们是一个中心节点介导细胞因子激活和效应器功能之间的联系。对于 GM-CSF，MTs1 和 2 是而对于 IL-4 来说，它是必需的，而 MT3 则是必需的。在本提案中，我们将在我们期间开展的工作的基础上最后一个资助周期并深入探讨MT-锌轴如何调节GM-CSF的活性和 IL-4 对人和小鼠 Mo/Mɸ 的影响。我们收集了糖酵解控制的令人兴奋的数据受感染的 GM-CSF 刺激的 Mo/Mɸ 中 MTs1 和 2 的表达。另一方面，MT3 则调和了 IL-4 的糖酵解反应在这些细胞中被激活。目标 1 将破译糖酵解是如何形成的 MT1&2 表达和细胞内 Zn2+ 分布可增强 Mo/Mɸ 效应器功能。目标2 将定义 GM-CSF 激活的 Mo/Mɸ 的细胞内改变，从而拒绝真菌进入锌以及 MTs1&2 对这些吞噬细胞发挥的宿主防御的体内作用。目标3将阐明糖酵解和 MT3 在塑造 IL-4 生理学中的交叉点组织胞浆菌感染的 Mo/Mɸ。这些研究将为细胞因子调节提供新的见解组织胞浆菌感染的 Mo/Mɸ 的代谢和金属生物学。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Investigation of an optimal cell lysis method for the study of the zinc metalloproteome of Histoplasma capsulatum.

DOI：
10.1007/s00216-017-0556-7
发表时间：
2017-10
期刊：
Analytical and bioanalytical chemistry
影响因子：
4.3
作者：
Donnell AM;Lewis S;Abraham S;Subramanian K;Figueroa JL;Deepe GS Jr;Vonderheide AP
通讯作者：
Vonderheide AP

The intersection of host and fungus through the zinc lens.

宿主和真菌通过锌透镜的交叉点。